This application is a 371 of PCT/JP99/05463 filed Oct. 05, 1999.
The present invention relates to a tablet and a tablet production method, specifically to a tablet of which active substance (namely medicament) is kept stably without being affected by lubricant in case active substance is colored, decomposed or deteriorated in its potency, when such active substance touches lubricant, and to its production method.
A tablet is a widely used because it is convenient for carrying and dosing and is easy to be taken for an elder person or a child because it doesn""t float on the water when dosing with water.
Lubricant powder other than active substance powder, adjuvant powder and so on is added in molding material (powdered or granular material) to be compressed and tabletted in order to prevent grinding between punches and dies of a molding machine while tabletting and to prevent tabletting problems such as sticking, laminating and capping of produced tablets.
The present inventors have found that some active substances are colored, decomposed or deteriorated in their potencies when such active substances touch lubricant.
In order to avoid such phenomenon, it can be expected to tablet molding material without adding lubricant. However, grinding between punches and dies of a molding and tabletting problems such as sticking, laminating and capping of produced tablets are caused and as a result continuous tabletting can""t be executed.
Therefore, under the present situation, lubricant is usually added in molding material giving a preference to industrial production basis even though a tablet is colored or stability of active substance in a tablet is deteriorated.
However, it isn""t desirable because colored tablet causes a patient and health personnel such as a doctor and a pharmacist anxiety when such a tablet can be observed from outside like a naked tablet. Further, when potency of active substance in a tablet is deteriorated, objective clinical effect of the tablet may not be adequately brought out.
The present invention has been proposed to solve the above-mentioned problems. The object of the invention is to provide a tablet in which active substance doesn""t touch lubricant and grinding between punches and dies of a molding machine and tabletting problems such as sticking, laminating and capping when producing tablets aren""t caused in case active substance included in the tablet is colored, decomposed or deteriorated in its potency when such active substance touches lubricant and to provide a method for producing such a tablet.
According to the tablet of the present invention, it includes active substance affected by lubricant and is comprised of compressed mixture of active substance and adjuvant except for lubricant, and lubricant exists only on the surface of the tablet but isn""t included in the tablet.
The term xe2x80x9cactive substance affected by lubricantxe2x80x9d in this specification means active substance which is colored, decomposed or deteriorated in its potency when such active substance touches lubricant.
It is difficult to specify such active substance, however, it includes active substances of which coloring degree of a mixture of active substance, adjuvant except for lubricant, and lubricant after a fixed time is larger than that of a mixture of active substance and adjuvant except for lubricant comparing with that at a start time, or content of active substance in a mixture of active substance, adjuvant except for lubricant, and lubricant after a fixed time is larger than that in a mixture of active substance and adjuvant except for lubricant comparing with that at a start time when coloring degree test (absorbance analysis, color analysis and so on) and stability test are performed respectively.
Further, xe2x80x9cactive substance affected by lubricantxe2x80x9d includes active substance which is affected by moisture in air, proton and so on produced in a tablet, and lubricant.
The term xe2x80x9cadjuvant except for lubricantxe2x80x9d in this specification is material used for producing a tablet and means material other than lubricant.
More specifically, xe2x80x9cadjuvant except for lubricantxe2x80x9d may include excipient (filler) for increasing the amount for facilitating handling and for giving required volume as pharmaceutical drugs, binder, disintegrator, and other substance if required, except for lubricant.
xe2x80x9cLubricantxe2x80x9d in this specification includes lubricant in narrow sense which is added in molding material for dispersing force applied between powdered particle of molding material at a time of compression (tabletting) and for preventing adhering of powdered material on the punches and dies of a tabletting machine, and also includes glidants which is added in molding material for improving fluidity of molding material.
Such lubricant isn""t limited if it is usually used and may include light anhydrous silicic acid, stearic acid, and stearic acid metal salt.
Preferable examples of lubricants are stearic acid metal salt (Mg salt, Ca salt, Al salt, K salt, Na salt) and metal salt such as hydrated aluminum silicate, preferable examples of glidants are metal salt (oxide) such as talc and so on.
The lubricant existing on the surface of the tablet isn""t applied on purpose. A part of lubricant applied on the surfaces of the punches and the dies of the tabletting machine used for tabletting is attached on the surface of the tablet at the time of compressing.
As such a tablet doesn""t include lubricant therein, the active substance included in the tablet doesn""t touch lubricant. Therefore, the active substance isn""t colored, decomposed or its potency isn""t deteriorated so that the active substance can show high stability.
According to the tablet of the present invention, the active substance affected by lubricant is chemical substance having functional group.
The term xe2x80x9cfunctional groupxe2x80x9d in this specification includes carboxyl group, amino group, hydroxyl group, ester group, amide group, phosphate group, carbonyl group, sulfonyl group, sulfonyloxy group, guanidyl group, sulfonamide group, halogen (chlorine, fluorosis, iodine, bromine and so on) and so on.
If lubricant is above-mentioned metal salt and active substance having such functional group touches the lubricant, the active substance reacts with metal component (magnesium, calcium and so on) of the lubricant so that it is colored, decomposed or its potency is deteriorated.
However, as the tablet doesn""t include lubricant therein, active substance, namely chemical substance having functional group doesn""t touch the lubricant. Therefore, the active substance included in the table is stably kept without being colored, decomposed or deteriorating its potency.
According to the tablet in the present invention, the active substance affected by lubricant may be one of ascorbic acid and acetylsalicylic acid.
Ascorbic acid and acetylsalicylic acid are accelerated to be decomposed and colored by stearic acid metal salt (Mg salt, Ca salt), hydrated aluminum silicate, and talc. However, as the tablet doesn""t include lubricant therein, ascorbic acid and acetylsalicylic acid included in the tablet doesn""t touch the lubricant. Therefore, ascorbic acid and acetylsalicylic acid in the tablet aren""t colored, decomposed or their potency isn""t deteriorated so that the active substance can be kept stably.
According to the tablet in the present invention, a formulation of the active substance is granule, a formulation of the adjuvant except for lubricant is granule, and the active substance granule and the adjuvant granule are substantially same in particle diameter.
The term xe2x80x9cgranulexe2x80x9d in this specification is a granulated material in which powdered material is grown to be with a fixed particle diameter using binder according to a fluid-bed granulation method.
The phrase xe2x80x9cthe active substance granule and the adjuvant granule are substantially same in particle diameterxe2x80x9d more specifically means that the average particle diameter and the particle size distribution of the active substance granule and the adjuvant granule are substantially same.
As a mixture of active substance granule and adjuvant granule, not a mixture of active substance powder and adjuvant powder, is compressed, active substance granule and/or adjuvant granule are deformed or broken so that mechanical force applied therein can be dispersed.
Therefore, pressure caused by compressing doesn""t concentrate on active substance granule so that tabletting can be achieved without denaturing the active substance even if physical property and chemical property of the active substance is apt to be denatured by high pressure.
As the particle diameter of the active substance granule and that of the adjuvant granule in the tablet are substantially same, those granules are spontaneously mixed uniformly in mixing process.
Further, when the mixture is filled in the die to which a lower punch is inserted to a fixed position at a material charge point of a rotary type tabletting machine, active substance granule doesn""t substantially cause particle segregation in the mixture filled in the die.
Namely, active substance granule is homogeneously dispersed in a tablet.
Therefore, such a tablet is superior as a dividable tablet.
The tablet production method of the present invention comprises the steps of producing mixture of active substance affected by lubricant and adjuvant except for lubricant, mixing lubricant powder with positive pulsating vibration air for dispersion, spraying the lubricant powder dispersed by the positive vibration air on a lower surface of an upper punch, an upper surface of a lower punch and an inner circumferential wall of a die, and tabletting the mixture by means of the upper and lower punches and the die.
The term xe2x80x9cpulsating vibration airxe2x80x9d in this specification means air of which pressure is changed in time.
More specifically, xe2x80x9cpulsating vibration airxe2x80x9d means air wave of which high pressure part (peak) and low pressure part (valley) are alternately shown at a fixed period.
The term xe2x80x9cpositive pressurexe2x80x9d in this specification means that air pressure in the tablet production system used in the present invention is higher than atmospheric pressure out of the system.
The term xe2x80x9cpositive pulsating vibration airxe2x80x9d may include pulsating vibration air of which both peak and valley are positive and pulsating vibration air of which peak is positive pressure and valley is substantially equal to the atmospheric pressure out of the tabletting machine.
When positive pulsating vibration air is used for mixing lubricant powder with air for dispersion, lubricant powder is well dispersed by air comparing with the case when lubricant powder is dispersed by air having constant pressure.
Thus according to the tablet production method of the present invention, as lubricant powder dispersed by positive pulsating vibration air for dispersion is sprayed on the lower surface of the upper punch, the upper surface of the lower punch and the inner circumferential die wall, lubricant powder is uniformly applied thereon.
As a result, even if lubricant isn""t added in the molding material, grinding between the upper punches, the lower punches, and the dies while tabletting and tabletting problems such as sticking, laminating, capping and so on aren""t caused.
Therefore, according to such a tablet production method, a tablet which isn""t colored and doesn""t cause any deterioration of the potency of the active substance contained in the tablet during a storage of the tablet can be easily produced in case such active substance contained in the tablet is affected by lubricant, because lubricant isn""t required to be added in molding material.
According to the tablet production method of the present invention, the spraying step is comprised of substantially vertically spraying at a blast the lubricant powder dispersed by the positive pulsating vibration air onto the upper surface of the lower punch when the lower punch is inserted in a predetermined position of the die, producing upward air flow directing substantially vertically for the lower surface of the upper punch around the lower surface of the upper punch, and gradually spraying the lubricant powder dispersed by the positive pulsating vibration air onto the lower surface of the upper punch while carrying the lubricant powder by the air flow.
According to such a tablet production method, lubricant powder dispersed by positive pulsating vibration air is sprayed at a blast on the upper surface of the lower punch on which extra lubricant is apt to be piled by gravitation so as to shorten the time for exposing the upper surface of the lower punch to lubricant powder. Further, extra lubricant powder piled on the upper surface of the lower punch by gravitation is blown out from the upper surface of the lower punch. Therefore, powder lubricant is uniformly applied on the upper surface of the lower punch.
Moreover, as part of lubricant blown from the upper surface of the lower punch is designed to be attached on the inner circumferential wall of the die into which the lower punch is inserted at a predetermined position, almost the same amount of lubricant as the amount applied on the upper surface of the lower punch is uniformly attached on the inner circumferential wall of the die on which lubricant has difficulty to be applied comparing with the upper surface of the lower punch.
As for the lower surface of the upper punch on which lubricant powder is difficult of applying, air flow going upward in almost vertical direction against the lower surface of the upper punch is generated around the lower surface of the upper punch.
Therefore, lubricant powder dispersed by positive pulsating vibration air flow sequentially runs into the lower surface of the upper punch to be applied thereon carrying the lubricant powder by the upward air flow.
Further according to the tablet production method, the lower surface of the upper punch is designed to be exposed in lubricant powder longer comparing with the upper surface of the lower punch. Almost the same amount of lubricant powder is uniformly applied on the lower surface of the upper punch by adjusting the exposure time like the upper surface of the lower punch, and the inner circumferential die wall.
Thus almost the same amount of lubricant powder is uniformly applied on the lower surface of the upper punch, the upper surface of the lower punch, and the inner circumferential die wall, so that molding material doesn""t adhere on the punches and dies while tabletting if lubricant isn""t added in the molding material. As a result, because grinding between punches and dies of a molding machine and tabletting problems such as sticking, laminating and capping of produced tablets are further prevented, continuous tabletting of molding material can be more completely achieved and a tablet without containing lubricant therein can be produced at high productivity.
Therefore, as a tablet without containing lubricant therein can be produced easily and at high productivity according to the present invention, the tablet which isn""t colored, or deteriorated in its potency during the storage of the tablet even if active substance contained in the tablet is affected by lubricant.